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Authors: Arthur S. Tischler, M.D., Anastassios G. Pittas, M.D.
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1. Case 1 Answers – type 1 diabetes, normal Pancreas

  1. Answer A. Teaching Aim: To understand the pathophysiology of diabetic ketoacidosis (DKA). DKA is a state occurring in the setting of absolute insulin deficiency. In the absence of insulin, there is mobilization of energy stores from peripheral tissues to the liver: amino acids from muscle are converted to glucose and fatty acids from adipose tissue are converted to ketones. Low insulin/glucagon ratio promotes production of ketones. Acetoacetate and beta-hydroxybutyric acid are the main ketone bodies with the latter making up the majority of circulating ketones in the acute state. The serum test for ketones, however, detects acetoacetate only. Decreased peripheral utilization of glucose and ketones due to the absence of insulin further contribute to the accumulation of glucose/ketones. Accumulation of ketoacids leads to an anion gap metabolic acidosis. A large amount of potassium is lost in the urine through osmotic diuresis from glycocuria. The K level may appear normal due to the K shift from intracellular to extracellular space that occurs with acidosis. One must always look for a precipitating cause for DKA. The precipitating cause is most often infection, failure to take one's insulin or another metabolic stress such as an myocardial infarction or stroke. Frequently, however, no underlying cause is determined. DKA is a life-threatening emergency with mortality up to 5%.
  2. To understand the management of DKA. In this patient, DKA appears to have occurred in the setting of pneumonia and a possible missed insulin dose. The patient should start off by receiving aggressive hydration with normal saline along with an insulin drip. Electrolytes and fluid status should be monitored every 1-2 hours initially using a careful flow sheet. When the blood glucose decreases to about 250 mg/dl, the IV fluids should be changed to 5% dextrose NS or 1/2 NS. The insulin drip should be continued until the acidosis is close to resolution. Acidosis cannot be adequately monitored by checking serum ketones as beta-hydroxybyturate is not measured by the assay. The best test is the pH, but since this requires collection of arterial blood which is painful, the anion gap is followed. As the hyperglycemia and the acidosis improve in the presence of insulin, K administration will be necessary together with the IV fluids. Bicarbonate is generally not given unless the pH is under 7.0-7.1 as ketoacids will metabolize to bicarbonate if they are not excreted in the urine. Administration of phosphate is not required unless the serum phosphorus is extremely low. Possible complications during treatment include cerebral edema in children, ARDS, thrombosis, hyperchloremic acidosis (not really a problem) and overshoot alkalosis from bicarbonate therapy.
  3. To appreciate the importance of intensive insulin therapy. Intensive insulin therapy of type 1 diabetes involves the use of multiple insulin shots per day or continuous subcutaneous insulin infusion (CSII, insulin pump therapy). Intensive insulin therapy involves using a combination of "basal" and "bolus" insulin in an attempt to mimic the normal physiology of the pancreatic beta islet cells. When using multiple shots per day, "basal" insulin is either intermediate (NPH/Lente) or long acting insulin (Ultralente) and "bolus" is short (regular) or rapid acting insulin (lispro or aspart). The "basal" insulin is used one or more times per day (usually twice) as background insulin while the "bolus" insulin is used at mealtimes. CSII uses short or rapid acting insulin within a pump. Basal rates and boluses for meals are programmed by the patient. The pump is attached to the patient via an infusion catheter into the subcutaneous tissue of the abdomen and the infusion set is changed every 2-3 days. Intensive insulin therapy in type 1 diabetics has been shown by the Diabetes Complications and Control Trial (DCCT) to lower the risk of microvascular complications as compared to insulin regimens that use fewer than 3 shots per day. In this study, the intensive control group achieved an HbA1C value of 7.2% (normal up to 6%). The study looked at primary prevention (patients without the complication at the start of the study) and secondary (patients with the complication at the start) prevention i.e. worsening of retinopathy, nephropathy and neuropathy. The DCCT cohort were treated over an average of 6.5 yr.
    Complication Primary Prevention Risk Reduction Secondary Prevention Risk Reduction
    Retinopathy 76% 56%
    Nephropathy 34% 56%
    Neuropathy 69% 57%

    Intensive control in the DCCT was associated with a >3 fold risk for severe hypoglycemic events and a significant increase in body weight.
  4. Answer B. The presence of auto-antibodies to islet cell antigens is the best predictor of future development of type 1 diabetes. However, most people with antibodies will not develop the disease and there is nothing to do that has been proven to prevent the disease.
  5. PATH – Normal pancreatic islets contain 4 cell types:
    A (Alpha) (glucagon): 15- 20%
    B (Beta) (insulin): 60 - 70%
    D (Delta) (somatostatin): 5%
    PP (pancreatic polypeptide): 2-5%

The great majority of pancreatic endocrine cells are located in “ordinary” islets, which are spherical structures evenly distributed in the tail, body and anterior portion of the head of the pancreas. In ordinary islets the cells are represented in the proportions shown above and are arranged in a characteristic micro-architecture (central B cells, “mantle” of A cells and interposed D and PP cells) that is thought to permit paracrine interactions. The posterior portion of the head of the pancreas, which is derived from the “ventral primordium” during embryogenesis, contains large, irregularly shaped islets consisting of up to 70% PP cells. Because of their size and shape, those islets may be mistaken for islet cell hyperplasia. In addition to forming islets, endocrine cells, mostly of the PP type, are scattered in small numbers throughout the pancreatic parenchyma and in the pancreatic ducts.

Initial findings in the pancreatic islets in type l diabetes are described as “insulitis”- a predominantly lymphocytic infiltrate consisting mostly of T-lymphocytes with some B-lymphocytes and macrophages. After ~ 1year, inflammation is gone and the islets show selective loss of insulin-producing cells, while other cell types persist or appear more prominent. These changes can be demonstrated by immunohistochemistry. The islets are often small and may be difficult to identify in H&E sections. Interestingly, in long-standing type l diabetes the whole pancreas may decrease in size and show atrophy of the acinar cells. This change has been attributed to loss of trophic stimulation by insulin.

2. Case 2 Answers – type 2 diabetes, Pancreas with hyalinization of Islets

  1. Answer D. According to the most recent NIH Obesity Guidelines, this woman would be classified as morbidly obese with a body mass index (BMI) of 47.6. This can be calculated as either:

    kg /m2OR (lb.. x 703)/ inches

    By these guidelines, optimal BMI is suggested to be between 18 and 25, overweight is 25-30, obesity is 30-40 and severe obesity is over 40.
  2. Answer C. To review the diagnosis of diabetes. The diagnosis of type 2 diabetes can be made in 3 ways: Fasting Plasma Glucose >126 mg/dl, Glucose > 200 mg/dl 2 hours following ingestion of 75 g of glucose, Plasma Glucose > 200 mg/dl coupled with symptoms of diabetes. Unless the glucose level is unequivocally elevated and the patient has symptoms, these tests should be repeated prior to making the diagnosis of diabetes.
  3. Answer B. To review risk factors for type 2 diabetes. BMI is the most significant risk factor in most people with type 2 diabetes.
  4. Answer B. False, although rare monogenic causes of type 2 diabetes have been described, in most people the disease is polygenic in origin.
  5. To review management of type 2 diabetes and obesity based on pathophysiologic principles. Lifestyle interventions (diet and exercise) for 3 months is usually tried for newly diagnosed mild type 2 diabetes. A reasonable weight loss goal would be a 5-10% of initial weight or decrease in BMI by 2 units over a period of 6 or more months. Patients at risk for diabetes who lose 5-7% of their weight will decrease their chance of getting diabetes by 58%. If this initial weight loss goal is reached, she should strive for at least weight maintenance and, if possible, slow continued weight loss of a few lb. per month. Nutritional recommendations would include a balanced low calorie diet with a calorie range of 1500-1800 calories per day or at least a 500 calorie per day deficit between caloric intake and caloric expenditure. One balanced method to achieve a 500 calorie deficit would be to lower her current caloric intake by 250 calories while increasing her expenditure by 250 calories. This increase in expenditure could be created by a daily walk of about 30 minutes at her current weight (as she loses weight, the same walk would burn fewer calories). In addition to this aerobic activity, some low level strength training might also be recommended (especially in women) to help maintain muscle mass which is more efficient at burning calories than is adipose tissue. In patients with insulin resistance, the proportion of carbohydrates might be decreased (40-50% of calories) especially if the serum triglycerides are elevated. The majority of the carbohydrates in the diet should be whole grain, high fiber carbohydrates. These have been associated in recent studies with a lower risk for developing diabetes in those without it. It is important that patients be aware that all carbohydrates (not just "sugars") can raise serum blood sugar. Portion sizes of carbohydrates should be emphasized. Some would also recommend that the amount of monounsaturated fat in the diet be increased while keeping the total fat to about 30% of all calories. Monounsaturated fats have been associated with an improvement in the lipid profile (lower TG, higher HDL) and perhaps an improvement in insulin resistance.

    There are several adjuvant treatments that may assist this woman's weight loss and may improve her ability to maintain the lost weight. Sibutramine (Meridia) is an appetite suppressant medicine which works as a serotonin and norepinephrine reuptake inhibitor. Orlistat (Xenical) is a gastrointestinal lipase inhibitor which works by inhibiting the absorption of about 30% of the fat present in a meal.

    Gastric bypass surgery is an option to assist in weight loss for patients with BMI over 40 or over 35 with complications. This surgery has evolved over years and presently the most common surgery performed is a Roux-en-Y operation with construction of a small gastric pouch from the existing stomach and a bypass of about 50 cm of proximal small intestine. The jejunum is anastomosed to the outlet of the gastric pouch. Patients should be screened by a behavioral specialist familiar with the surgery and weight issues and should be able to demonstrate the skills associated with successful weight loss and weight maintenance prior to having the surgery. For many patients, preoperative weight loss of up to 10% may be necessary to allow for easier surgery. Total weight loss in patients who have the surgery may average 30-35% of their peak weight. Diabetics who have this surgery most often become "diet" controlled at weight nadir.

    The final adjuvant option that may be used in certain situations is a Very Low Calorie Diet (VLCD). This consists of either a specially formulated total liquid diet or high lean protein food based diet with fewer than 1200 calories per day (generally 800-1200 cal/d). VLCDs must be closely monitored due to the rapid weight loss with electrolytes, orthostatic blood pressures and intermittent EKGs.
  6. Answer F. To appreciate that there is no correct way of managing type 2 diabetes. Treatment must be based on the underlying pathophysiology. Lifestyle interventions should be emphasized but the patient should be treated with a pharmacologic agent at this point. Insulin is probably the most effective agent but insulin therapy is complex for both patient and health care providers. Based on her body habitus, she probably has insulin resistance so an insulin sensitizer is a good choice. A combination of an insulin secretagogue and insulin sensitizer is becoming a popular choice for monotherapy although there is no data to support its superiority over the more traditional approach of starting with one drug and adding more as needed.
  7. To learn that the goals for lipids in a diabetic, with or without known heart disease, are similar to those of a non diabetic with known heart disease. The goal LDL cholesterol is less than 100 mg/dl, triglycerides under 200 mg/dl (and possibly under 100-150 mg/dl according to some experts) and HDL cholesterol over 35 mg/dl. These goals are often difficult to achieve. A "statin" is the drug of choice for lowering LDL cholesterol and will have some effect on lowering triglycerides and raising HDL. A fibric acid derivative will lower triglycerides and raise HDL primarily and should be used first if LDL is near goal. Optimal diabetic control and weight loss should be emphasized.
  8. PATH – The islets in type 2 diabetes may appear normal, particularly early in the disease. Ultimately, 80-90% of patients (versus ~3% of patients with no apparent history of diabetes) will show islet amyloidosis (“islet hyalinization”). Islet amyloid polypeptide (amylin) is a 37 amino acid polypeptide synthesized by insulin-producing cells and deposited extracellularly as amyloid between the cells and islet capillaries. Amyloid accumulation often pushes aside and then replaces first the insulin-producing cells and sometimes all of the islet cells. The islets are unevenly affected. Some may therefore appear normal while others show advanced amyloid deposition. The irregular PP islets in the posterior head of the pancreas are unaffected, probably explaining an incorrect belief expressed in older literature that islet cell hyperplasia may occur in type 2 diabetes. An additional finding now seldom seen is “hydropic change”- swelling due to glycogen accumulation in beta cells of patients with prolonged hyperglycemia and diabetic coma.

3. Case 3 Answers - Parathyroid Adenoma

  1. Answer A. The most common etiologies for hypercalcemia are hyperparathyroidism (seen in outpatients) and hypercalcemia of malignancy (seen in inpatients with cancer). The causes can generally be divided in PTH dependent vs. PTH independent. A PTH level is therefore very helpful in differentiating among the most common causes.
  2. Answer A. Discuss how the PTH and urine calcium measurement helps with differentiating between the causes of hypercalemia including hypercalcemia of malignancy. High calcium and high PTH suggest primary hyperparathyroidism. However, other etiologies may share this profile so additional testing is required. Discuss mechanisms of hypercalcemia of malignancy which include PTH-rP (PTH-related peptide) secreted by many carcinomas including squamous cell tumors (lung, head and neck), local osteolytic release of cytokines and local bone breakdown, 1-hydroxylase expression in lymphoma leading to high levels of 1,25 OH vitamin D and hyperabsorption of calcium. PTH-rP is a different gene product than PTH but the first 13 amino acids are identical to PTH and activates the PTH receptor. Thus, PTH-rP causes hypercalcemia and hypophosphatemia. PTH-rP is not associated with bone metastases.
  3. PATH - Hyperplasia, by definition, involves multiple parathyroid glands. Discuss pathophysiology of adenoma vs. hyperplasia.
  4. PATH - The right lower gland was biopsied in order to prove that it was normocellular.
  5. PATH - A normal parathyroid generally weighs 30 to 40 mg
  6. PATH – B. False. Parathyroid adenomas frequently contain patchy areas of cells with differing architecture or cytology. This may reflect clonal evolution of tumor cell populations.
  7. Yes, hypocalcemia is an emergency. This patient has many symptoms and signs of hypocalcemia including perioral numbness and acroparesthesias. On exam, she will probably exhibit the characteristic Chvostek sign (twitching of the facial muscles) and Trousseau's sign (tetany of the hand and wrist especially during arterial occlusion during a BP measurement). With worsening of hypocalcemia, laryngospam may occur with inability to breathe and the patient may also have a seizure and mental status changes.
  8. Answer A. The differential diagnosis of hypocalcemia includes PTH deficiency or resistance or vitamin D deficiency or resistance as well as other less common etiologies. The most common cause is surgical hypoparathyroidism, vitamin D deficiency, kidney disease. Her hypocalcemia is due to PTH deficiency as her remaining glands were atrophied in the presence of an adenoma and have not had enough time to recover function after removal of the adenoma.

Vitamin D is synthesized in the skin from cholesterol precursor after exposure to sunlight. In the Northeast, vitamin D may not be efficiently synthesized between October and April. Vitamin D synthesized in the skin is then hydroxylated to 25-OH vitamin D by the liver. 25-OH vitamin D is the storage form of vitamin D. 25-OH vitamin D is hydroxylated to 1,25-OH vitamin D by the kidney under stimulation by PTH. The patient's 1,25-OH vitamin D levels should be relatively low in the setting of low PTH. Magnesium affects secretion and action of PTH, so a magnesium level should be checked.

1,25-OH vitamin D is necessary for calcium absorption from the gut. Routine supplementation in Northern climates is 400 I.U./day of vitamin D in the form of ergocalciferol but probably higher supplementation is required especially in those with osteoporosis, malabsorption, or elderly (>65 years) should be given 800 I.U./day. The half-life of 25-OH vitamin D is very long while the half life of 1,25-OH vitamin D is short; therefore, the best measure of vitamin D status is to measure the 25-OH vitamin D. In patients with hypoparathyroidism and those with significant hypocalcemia should be given a short-acting, synthetic form of bioactive 1,25-OH vitamin D, Calcitriol.

4. Case 4 Answers – Parathyroid Hyperplasia and MEN1,

  1. The family history supports a diagnosis of MEN type 1, which is characterized by the presence of parathyroid hyperplasia or neoplasia (~80-100% of patients) pancreatic endocrine neoplasms (~80-100 %) and pituitary adenomas (~20-65%). This syndrome may also include neuroendocrine tumors in the duodenum or, less often, the stomach. It is inherited as an autosomal dominant trait.
  2. The MEN 1 gene has been identified as a tumor suppressor gene localized to chromosome 11q13, encoding a 67 kDa protein known as Menin. Normal menin is a widely distributed, mainly nuclear protein that may partner with junD, NF-kB, or other transcription factors. It has also been reported to associate with several cytoplasmic proteins including components of the cytoskeleton. Its signaling pathways remain unclear. Germline or somatic mutations in MEN1 cause truncation or absence of menin encoded by one allele, while loss of heterozygosity of 11q13 in tumors causes inactivation of the other MEN1 copy. Somatic mutations of MEN1 are common in nonhereditary tumors that are part of the MEN1 spectrum. There are no identified mutation “hotspots” for germline or somatic mutations and little or no genotype/phenotype correlation.
  3. PATH - The gland shows evidence of diffuse hyperplasia.
  4. PATH - The large pink cells are oncocytes (mitochondria rich cells).
  5. PATH - Chief cells are smaller than oncocytes and have a clearer cytoplasm.
  6. PATH - There is no compressed rim of parathyroid.